US9370584B2ExpiredUtilityA1
CA6 antigen-specific cytotoxic conjugate and methods of using the same
Est. expiryJul 21, 2023(expired)· nominal 20-yr term from priority
C07K 14/4727C07K 2317/56C07K 16/3092C07K 16/303A61K 39/39558C07K 2317/24C07K 2317/567C07K 2317/565C07K 16/3015A61K 31/537C07K 2317/14A61K 2039/505A61K 47/6877C07K 16/464C07K 2317/92A61K 47/6859A61P 35/00A61K 47/6855C07K 16/3069A61K 47/6851A61K 47/6869C07K 2317/73A61K 47/6809C07K 14/4748A61K 47/48384A61K 47/48569A61K 47/48407A61K 47/68033A61K 47/6803
72
PatentIndex Score
1
Cited by
88
References
90
Claims
Abstract
Cytotoxic conjugates comprising a cell binding agent and a cytotoxic agent, therapeutic compositions comprising the conjugate, methods for using the conjugates in the inhibition of cell growth and the treatment of disease, and a kit comprising the cytotoxic conjugate are disclosed are all embodiments of the invention. In particular, the cell binding agent is a monoclonal antibody, and epitope-binding fragments thereof, that recognizes and binds the CA6 glycotope. The present invention is also directed to humanized or resurfaced versions of DS6, an anti-CA6 murine monoclonal antibody, and epitope-binding fragments thereof.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A method of treating a subject having a cancer expressing CA6 glycotope, said method comprising, administering a therapeutically effective amount of a conjugate to said subject, wherein said conjugate comprises a cell binding agent and a cytotoxic agent, wherein said cell binding agent comprises an antibody or epitope-binding fragment thereof comprising at least one heavy chain variable region and at least one light chain variable region, wherein said heavy chain variable region comprises three complementarity-determining regions having amino acids 31-35, 50-66, and 99-106 of SEQ ID NO:11, respectively, and wherein said light chain variable region comprises three sequential complementarity-determining regions having amino acids 24-33, 49-55, and 88-96 of SEQ ID NO:8, respectively, wherein the cell binding agent binds to the CA6 glycotope.
2. A method of treating a subject having a cancer expressing CA6 glycotope, said method comprising, administering a therapeutically effective amount of a conjugate to said subject, wherein said conjugate comprises a cell binding agent and a cytotoxic agent, wherein said cell binding agent comprises an antibody or epitope-binding fragment thereof comprising at least one heavy chain variable region and at least one light chain variable region, wherein said heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:10 or 11, wherein said light chain variable region comprises three sequential complementarity-determining regions comprising the amino acid sequences set forth in SEQ ID NOs:4-6, respectively, and wherein the cell binding agent binds to the CA6 glycotope.
3. A method of treating a subject having a cancer expressing CA6 glycotope, said method comprising, administering a therapeutically effective amount of a conjugate to said subject, wherein said conjugate comprises a cell binding agent and a cytotoxic agent, wherein said cell binding agent comprises an antibody or epitope-binding fragment thereof comprising at least one heavy chain variable region and at least one light chain variable region, wherein said light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:8, wherein said heavy chain variable region comprises three complementarity-determining regions comprising the amino acid sequences set forth in SEQ ID NOS:20-22, respectively, and wherein the cell binding agent binds to the CA6 glycotope.
4. The method of claim 3 , wherein said heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:10 or 11.
5. The method of claim 1 , wherein said antibody or epitope-binding fragment thereof is selected from the group consisting of a Fab fragment, a Fab′ fragment, a F(ab′) 2 fragment, a single-chain Fvs (scFv) fragment, a single-chain antibody, and a disulfide-linked Fvs (sdFv) fragment.
6. The method of claim 1 , wherein said cell binding agent and said cytotoxic agent are covalently linked through a PEG linking group.
7. The method of claim 1 , wherein said cell binding agent and said cytotoxic agent are covalently linked through a thiol or disulfide functionality of said cytotoxic agent.
8. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound DM1 of formula (I):
9. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound DM4 of formula (II):
10. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound of formula (III):
wherein:
Y′ represents
(CR 7 R 8 ) l (CR 9 ═CR 10 ) p (C≡C) q A 0 (CR 5 R 6 ) m D u (CR 11 ≡CR 12 ) r (C≡C) s B t (CR 3 R 4 ) n CR 1 R 2 SZ,
wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
A, B, D are cycloalkyl or cycloalkenyl having 3-10 carbon atoms, simple or substituted aryl or heterocyclic aromatic or heterocyclic radical;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical;
l, m, n, o, p, q, r, s, t, and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s t, and u are not zero at any one time; and
Z is H, SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical.
11. The method of claim 10 , wherein R 1 is methyl, R 2 is H and Z is H.
12. The method of claim 10 , wherein R 1 and R 2 are methyl and Z is H.
13. The method of claim 10 , wherein R 1 is methyl, R 2 is H, and Z is —SCH 3 .
14. The method of claim 10 , wherein R 1 and R 2 are methyl, and Z is —SCH 3 .
15. The method of claim 1 , wherein said cytotoxic agent is a maytansinoid compound selected from the group consisting of formulas (IV-L), (IV-D), and (IV-D,L):
wherein:
Y represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 SZ,
wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, or heterocyclic aromatic or heterocyclic radical;
l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0;
Z is H, SR or —COR wherein R is linear or branched alkyl or alkenyl having from 1 to 10 carbon atoms, cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical; and
May represents a maytansinoid which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.
16. The method of claim 15 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are each 1, n is 0, and Z is H.
17. The method of claim 15 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, l and m are 1, n is 0, and Z is H.
18. The method of claim 15 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are each 1, n is 0, and Z is —SCH 3 .
19. The method of claim 15 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , and R 8 are each H, l and m are 1, n is 0, and Z is —SCH 3 .
20. The method of claim 15 , wherein the cytotoxic agent is represented by formula (IV-L).
21. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound formula (V):
wherein:
Y represents
(CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 SZ,
wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 , are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, or heterocyclic aromatic or heterocyclic radical; and
l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0;
Z is H, SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical.
22. The method of claim 21 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H; l and m are each 1; n is 0; and Z is H.
23. The method of claim 21 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, 1 and m are 1; n is 0; and Z is H.
24. The method of claim 21 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are each 1, n is 0, and Z is —SCH 3 .
25. The method of claim 21 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, l and m are 1, n is 0, and Z is —SCH 3 .
26. The method of claim 1 , wherein said cytotoxic agent is a maytansinoid compound selected from the group consisting of formulas (VI-L), (VI-D), and (VI-D,L):
wherein:
Y 2 represents
(CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 SZ 2 ,
wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 2 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 , are each independently H, CH 3 , C 2 H 5 , linear cyclic alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical
l, m and o are each independently an integer of from 1 to 5, and in addition n can be 0;
Z 2 is SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical; and
May is a maytansinoid.
27. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound of formula (VII):
or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3-10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical;
wherein:
Y 2 ′ represents
(CR 7 R 8 ) l (CR 9 ═CR 10 ) p (C≡C) q A 0 (CR 5 R 6 ) m D u (CR 11 ═CR 12 ) r (C≡C) s B t (CR 3 R 4 ) n CR 1 R 2 SZ 2 —,
wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear branched or alkyl or alkenyl having from 1 to 10 carbon atoms, cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
A, B, and D each independently is cycloalkyl or cycloalkenyl having 3 to 10 carbon atoms, simple or substituted aryl, or heterocyclic aromatic or heterocyclic radical;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical;
l, m, n, o, p, q, r, s, t and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s t and u are not zero at any one time; and
Z 2 is SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3-10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical.
28. The method of claim 27 , wherein R 1 is methyl and R 2 is H.
29. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound of formula (VIII):
wherein:
Y 1 ′ represents
(CR 7 R 8 ) l (CR 9 ═CR 10 ) p (C≡C) q A 0 (CR 5 R 6 ) m D u (CR 11 ═CR 12 ) r (C≡C) s B t (CR 3 R 4 ) n CR 1 R 2 S—,
wherein:
A, B, and D, each independently is cycloalkyl or cycloalkenyl having 3-10 carbon atoms, simple or substituted aryl, or heterocyclic aromatic or heterocyclic radical;
R 1 is methyl and R 2 is H or R 1 and R 2 are methyl;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical; and
l, m, n, o, p, q, r, s, t, and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s t, and u are not zero at any one time.
30. The method of claim 29 , wherein R 1 is methyl and R 2 is H.
31. The method of claim 29 , wherein R 1 and R 2 are methyl.
32. The method of claim 1 , wherein said cytotoxic agent is a maytansinoid compound selected from the group consisting of formulas (IX-L), (IX-D), and (IX-D,L):
wherein:
Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 S—, wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical;
l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0; and
May represents a maytansinol which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.
33. The method of claim 32 , wherein R 1 is methyl and R 2 is H or R 1 and R 2 are methyl.
34. The method of claim 32 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 and R 8 are each H; l and m are each 1; n is 0.
35. The method of claim 32 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, l and m are 1, n is 0.
36. The method of claim 33 , wherein the maytansinoid is represented by formula (IX-L).
37. The method of claim 34 , wherein the maytansinoid is represented by formula (IX-L).
38. The method of claim 35 , wherein the maytansinoid is represented by formula (IX-L).
39. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound of formula (X):
wherein:
Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 S—,
wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical;
l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0; and
May represents a maytansinol which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.
40. The method of claim 39 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are 1, and n is 0.
41. The method of claim 39 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , and R 8 are each H, l and m are 1, and n is 0.
42. The method of claim 1 , wherein said cytotoxic agent is DM1 or DM4.
43. The method of claim 1 , wherein said cytotoxic agent is the taxane formula (XI):
44. The method of claim 1 , wherein said cytotoxic agent is member selected from the group consisting of a maytansinoid compound, a taxoid compound, a CC-1065 compound, a dolastatin compound, a daunorubicin compound, and a doxorubicin compound.
45. The method of claim 1 , wherein said cell binding agent and said cytotoxic agent are covalently linked via a N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) linker, wherein said cytotoxic agent is DM4.
46. The method of claim 45 , wherein 1-10 DM4 molecules are linked to said cell binding agent.
47. The method of claim 4 , wherein said antibody or epitope-binding fragment thereof is selected from the group consisting of a Fab fragment, a Fab′ fragment, a F(ab′) 2 fragment, a single-chain Fvs (scFv) fragment, a single-chain antibody, and a disulfide-linked Fvs (sdFv) fragment.
48. The method of claim 4 , wherein said cell binding agent and said cytotoxic agent are covalently linked through a PEG linking group.
49. The method of claim 4 , wherein said cell binding agent and said cytotoxic agent are covalently linked through a thiol or disulfide functionality of said cytotoxic agent.
50. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound DM1 of formula (I):
51. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound DM4 of formula (II):
52. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound of formula (III):
wherein:
Y′ represents
(CR 7 R 5 ) l (CR 9 ═CR 10 ) p (C≡C) q A 0 (CR 5 R 6 ) m D u (CR 11 ═CR 12 ) r (C≡C) s B t (CR 3 R 4 ) n CR 1 R 2 SZ,
wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
A, B, D are cycloalkyl or cycloalkenyl having 3-10 carbon atoms, simple or substituted aryl or heterocyclic aromatic or heterocyclic radical;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical;
l, m, n, o, p, q, r, s, t, and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s t, and u are not zero at any one time; and
Z is H, SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical.
53. The method of claim 52 , wherein R 1 is methyl, R 2 is H and Z is H.
54. The method of claim 52 , wherein R 1 and R 2 are methyl and Z is H.
55. The method of claim 52 , wherein R 1 is methyl, R 2 is H, and Z is —SCH 3 .
56. The method of claim 52 , wherein R 1 and R 2 are methyl, and Z is —SCH 3 .
57. The method of claim 4 , wherein said cytotoxic agent is a maytansinoid compound selected from the group consisting of formulas (IV-L), (IV-D), and (IV-D,L):
wherein:
Y represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 SZ,
wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, or heterocyclic aromatic or heterocyclic radical;
l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0;
Z is H, SR or —COR wherein R is linear or branched alkyl or alkenyl having from 1 to 10 carbon atoms, cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical; and
May represents a maytansinoid which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.
58. The method of claim 57 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are each 1, n is 0, and Z is H.
59. The method of claim 57 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, l and m are 1, n is 0, and Z is H.
60. The method of claim 57 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are each 1, n is 0, and Z is —SCH 3 .
61. The method of claim 57 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , and R 8 are each H, l and m are 1, n is 0, and Z is —SCH 3 .
62. The method of claim 57 , wherein the cytotoxic agent is represented by formula (IV-L).
63. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound formula (V):
wherein:
Y represents
(CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 SZ, wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 , are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, or heterocyclic aromatic or heterocyclic radical; and
l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0;
Z is H, SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical.
64. The method of claim 63 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H; l and m are each 1; n is 0; and Z is H.
65. The method of claim 63 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, 1 and m are 1; n is 0; and Z is H.
66. The method of claim 63 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are each 1, n is 0, and Z is —SCH 3 .
67. The method of claim 63 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, l and m are 1, n is 0, and Z is —SCH 3 .
68. The method of claim 4 , wherein said cytotoxic agent is a maytansinoid compound selected from the group consisting of formulas (VI-L), (VI-D), and (VI-D,L):
wherein:
Y 2 represents
(CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 SZ 2 ,
wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 2 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 , are each independently H, CH 3 , C 2 H 5 , linear cyclic alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical
l, m and o are each independently an integer of from 1 to 5, and in addition n can be 0;
Z 2 is SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical; and
May is a maytansinoid.
69. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound of formula (VII):
or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3-10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical;
wherein:
Y 2 ′ represents
(CR 7 R 8 ) l (CR 9 ═CR 10 ) p (CC) q A 0 (CR 5 R 6 ) m D u (CR 11 ═CR 12 ) r (C≡C) s B t (CR 3 R 4 ) n CR 1 R 2 SZ 2 —,
wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear branched or alkyl or alkenyl having from 1 to 10 carbon atoms, cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
A, B, and D each independently is cycloalkyl or cycloalkenyl having 3 to 10 carbon atoms, simple or substituted aryl, or heterocyclic aromatic or heterocyclic radical;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical;
l, m, n, o, p, q, r, s, t and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s t and u are not zero at any one time; and
Z 2 is SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3-10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical.
70. The method of claim 69 , wherein R 1 is methyl and R 2 is H.
71. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound of formula (VIII):
wherein:
Y 1 ′ represents
(CR 7 R 8 ) l (CR 9 ═CR 10 ) p (C≡C) q A 0 (CR 5 R 6 ) m D u (CR 11 ═CR 12 ) r (C≡C) s B t (CR 3 R 4 ) n CR 1 R 2 S—,
wherein:
A, B, and D, each independently is cycloalkyl or cycloalkenyl having 3-10 carbon atoms, simple or substituted aryl, or heterocyclic aromatic or heterocyclic radical;
R 1 is methyl and R 2 is H or R 1 and R 2 are methyl;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical; and
l, m, n, o, p, q, r, s, t, and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s t, and u are not zero at any one time.
72. The method of claim 71 , wherein R 1 is methyl and R 2 is H.
73. The method of claim 71 , wherein R 1 and R 2 are methyl.
74. The method of claim 4 , wherein said cytotoxic agent is a maytansinoid compound selected from the group consisting of formulas (IX-L), (IX-D), and (IX-D,L):
wherein:
Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 S—, wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical;
l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0; and
May represents a maytansinol which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.
75. The method of claim 74 , wherein R 1 is methyl and R 2 is H or R 1 and R 2 are methyl.
76. The method of claim 74 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 and R 8 are each H; l and m are each 1; n is 0.
77. The method of claim 74 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, l and m are 1, n is 0.
78. The method of claim 75 , wherein the maytansinoid is represented by formula (IX-L).
79. The method of claim 76 , wherein the maytansinoid is represented by formula (IX-L).
80. The method of claim 77 , wherein the maytansinoid is represented by formula (IX-L).
81. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound of formula (X):
wherein:
Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m CR 3 R 4 ) n CR 1 R 2 S—,
wherein:
R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;
R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical;
l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0; and
May represents a maytansinol which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.
82. The method of claim 81 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are 1, and n is 0.
83. The method of claim 81 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , and R 8 are each H, l and m are 1, and n is 0.
84. The method of claim 4 , wherein said cytotoxic agent is DM1 or DM4.
85. The method of claim 4 , wherein said cytotoxic agent is the taxane formula (XI):
86. The method of claim 4 , wherein said cytotoxic agent is a member selected from the group consisting of a maytansinoid compound, a taxoid compound, a CC-1065 compound, a dolastatin compound, a daunorubicin compound, and a doxorubicin compound.
87. The method of claim 4 , wherein said cell binding agent and said cytotoxic agent are covalently linked via a N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) linker, wherein said cytotoxic agent is DM4.
88. The method of claim 87 , wherein 1-10 DM4 molecules are linked to said cell binding agent.
89. The method of claim 1 , wherein the cancer is selected from the group consisting of serous ovarian carcinoma, endometrioid ovarian carcinoma, neoplasm of the uterine cervix, neoplasm of the endometrius, neoplasm of the vulva, breast carcinoma, pancreatic tumor, and tumor of the urothelium.
90. The method of claim 4 , wherein the cancer is selected from the group consisting of serous ovarian carcinoma, endometrioid ovarian carcinoma, neoplasm of the uterine cervix, neoplasm of the endometrius, neoplasm of the vulva, breast carcinoma, pancreatic tumor, and tumor of the urothelium.Cited by (0)
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